Paraoxonase polymorphism (Gln192Arg) as a determinant of the response of human coronary arteries to serotonin.

Background-Oxidation of LDL plays a role in endothelial dysfunction. Paraoxonase, an enzyme present on HDL, protects LDL against oxidation. Paraoxonase activity is genetically determined in part, and 3 genotypes have been described with variable enzymatic activity. We hypothesized that the paraoxonase polymorphism might influence endothelial function. Methods and Results-Twenty-seven patients with clinical manifestations of coronary artery disease underwent provocative testing by intracoronary administration of serotonin. None of the coronary arteries studied had significant (>50%) stenosis. Ten patients had the QQ genotype and 17 had the QR genotype. At proximal segments, the mean percentage reduction in lumen diameter in response to serotonin was greater in QQ patients than in QR patients (10(-5) mol/L: P<0.05; 10(-4) mol/L: P<0.006). Similarly, at distal segments, constriction in response to serotonin was greater in QQ patients than in QR patients (10(-6) mol/L: P<0. 03; 10(-5) mol/L: P<0.07). Conclusions-These results suggest a higher synthesis or release of endothelium-derived relaxing factors to counteract the vasoconstrictor effect of serotonin in patients with the R allele. These findings provide evidence that the paraoxonase polymorphism may play a role in the regulation of coronary vasomotor tone.

Prognostic value of ventricular arrhythmias in systemic hypertension.

OBJECTIVE: Hypertensive left ventricular hypertrophy is associated with an increased risk of arrhythmias and mortality. However, no clinical study has demonstrated a significant relationship between ventricular arrhythmias and mortality in systemic hypertension. DESIGN AND METHODS: To evaluate the prognostic value of arrhythmogenic markers, we included, prospectively, 214 hypertensive patients aged (mean+/-SD) 59.1+/-12.8 years, without symptomatic coronary disease, myocardial infarction, systolic dysfunction or electrolyte disturbances. At inclusion, a 12-lead electrocardiogram (ECG) with QT dispersion calculation, a 24 h Holter ECG (204 patients) with Lown classification of ventricular arrhythmias, echocardiography (reliable in 187 patients) and a signal-averaged ECG (125 patients) with ventricular late potentials were recorded. RESULTS: At baseline, echocardiographic left ventricular hypertrophy was found in 63 patients (33.7%). Non-sustained ventricular tachycardia (Lown class IVb) was recorded in 33 patients (16.2%) and late potentials in 27 patients (21.6%). After a mean follow-up of 42.4+/-26.8 months, all-cause mortality was 11.2% (24 patients); 17 patients died of cardiac causes (7.9%); of these, nine (4.2%) died suddenly. In univariate analysis, age, Lown class IVb and a QT dispersion > 80 ms were significantly related to global, cardiac and sudden death (P < 0.01). The left ventricular mass index was related to cardiac mortality (P= 0.002). In multivariate analysis, only Lown class IVb was an independent predictor of global and cardiac mortality, increasing the risk of global death 2.6-fold (95% confidence interval 1.2-6.0) and cardiac death 3.5-fold (95% confidence interval 1.2-9.7). CONCLUSION: In hypertensive patients the presence of non-sustained ventricular tachycardia has prognostic value.

[Prognostic value of ventricular arrhythmia in hypertensive patients]. / Valeur pronostique des arythmies ventriculaires chez l'hypertendu.

OBJECTIVE: Hypertensive left ventricular hypertrophy (LVH) is associated with increased risk of arrhythmias and mortality. However, no clinical study demonstrated a significant relation between ventricular arrhythmias and mortality in systemic hypertension. DESIGN AND METHODS: To evaluate the prognostic value of arrhythmogenic markers in systemic hypertension, we included between 1987 and 1993. 214 hypertensive patients, 59.1 +/- 12.8 years old, without symptomatic coronary disease, myocardial infarction, systolic dysfunction, electrolyte disturbances or antiarrhythmic therapy. At inclusion, an ECG, a 24 h Holter ECG (204 patients) with Lown classification of ventricular arrhythmias, an echocardiography (reliable in 187 patients) with left ventricular mass index and ejection fraction calculation, a SAECG (125 patients, enrolled after 1988) with ventricular late potentials (LP) were recorded. QT interval dispersion (QTd) was calculated on 12 leads standard ECG and LVH was appreciated. RESULTS: At baseline echocardiographic LVH was recorded in 63 patients (33.7%) with normal ejection fraction (75 +/- 7.4%). Non-sustained ventricular tachycardia (Lown IVb) was found in 33 pts (16.2%) and LP in 27 patients (21.6%). After a mean follow up of 42.4 +/- 26.8 months, all-cause mortality was 11.2% (24 patients); 17 patients died of cardiac causes (7.9%); of these 9 patients (4.2%) died suddenly. In univariate analysis, age, strain pattern of LVH, advanced Lown classes and abnormal QT dispersion (> 80 ms) were significantly related to global, cardiac and sudden death (p < or = 0.01). Left ventricular mass index was closely related to cardiac mortality (p = 0.002). LP failed to predict mortality. In multivariate analysis, only Lown class IVb was an independent predictor of global and cardiac mortality, increasing the risk of global death 2.6 fold [1.2-6.0] (CI 95%) and the risk of cardiac death 3.5 fold [1.2-9.7] (CI 95%). CONCLUSIONS: In hypertensive patients the presence of non-sustained ventricular tachycardia on 24 h Holter has a prognostic value.

[Sudden death and chronic cardiac insufficiency]. / Mort subite et insuffisance cardiaque chronique.

Sudden death accounts for about 35% of the mortality of cardiac failure and its incidence does not decrease with the use of angiotensin converting enzyme inhibitors. Non-sustained ventricular tachycardia on Holter monitoring, late ventricular potentials and tachycardia induced by programmed ventricular stimulation have no formal predictive value of sudden death, underlining the varied character of the mechanisms underlying sudden death during cardiac failure. Sustained ventricular tachycardia degenerating to ventricular fibrillation is only one of the rhythmic factors implicated together with inaugural ventricular fibrillation, bradyarrhythmias and electromechanical dissociation. The underlying cardiac disease plays a role in the initiation of the fatal arrhythmia. In coronary artery disease, recurrent acute ischaemia is the principal trigger factor in patients who often have triple vessel disease. This explains the fact that classic markers of arrhythmia in the post-infarction period, which are only the reflection of the arrhythmogenic substrate of ventricular tachycardia, usually due to reentry around the fibrous scar of the infarct, are not valid in patients with progressive ischaemic cardiomyopathy. The most effective antiarrhythmic treatment in this type of patient is the prevention of ischaemia, when possible. In primary dilated cardiomyopathy, the mechanism underlying sudden death could be different at each stage. In NYHA Stages I and II, ventricular tachyarrhythmias could play a major part in unexpected sudden death in patients whose stable haemodynamic status suggested a more prolonged survival. The value of an implantable defibrillator would seem to be proved in this group of patients, at least in secondary prevention. In Stages III and IV, ventricular arrhythmias only indicate the degree of ventricular dysfunction and sudden death may follow bradyarrhythmias and electromechanical dissociation due to the precarious haemodynamic status.

[Twenty-four hour time and frequency domain variability of systolic blood pressure and heart rate in an experimental model of arterial hypertension plus obesity]. / Variabilité temporelle et fréquentielle de la pression artérielle et de la fréquence cardiaque au cours du nycthémère dans un modèle expérimental d'hypertension artérielle avec obésité.

Modifications of heart rate (HR) and systolic blood pressure (SBP) variabilities (V) have been reported in the human syndrome arterial hypertension plus insulin-resistance. The aim of this study was to characterize the 24 h SBPV and HRV in both time and frequency domains during weight increase in dogs fed ad libitum with a high fat diet. Implantable transmitter units for measurement of blood pressure and heart rate were surgically implanted in five beagle male dogs. BP and HR were continuously recorded using telemetric measurements during 24 hours, before and after 6 and 9 weeks of hypercaloric diet in quiet animals submitted to a 12h light-dark cycle. To study nychtemeral cycle of SBP and HR, two periods were chosen: day (from 6.00 h to 19.00 h) and night (from 23.00 h to 6.00 h). Spontaneous baroreflex efficiency was measured using the sequence method. Spectral variability of HR and SBP was analyzed using a fast Fourier transformation on 512 consecutive values and normalized units of low (LF: 50-150 mHz, reflecting sympathetic activity) and high (HF: respiratory rate +/- 50 mHz, reflecting parasympathetic activity) frequency bands were calculated. The energy of total spectrum (from 0.004 to 1 Hz) was also studied. Body weight (12.4 +/- 0.9 vs 14.9 +/- 0.9 kg, p < 0.05). SBP (132 +/- 1 vs 147 +/- 1 mmHg, p < 0.05) significantly increased after 9 weeks of hypercaloric diet. A nycthemeral HR rhythm was present at baseline (day: 79 +/- 1 vs night: 71 +/- 1 bpm) but not after 9 weeks (day: 91 +/- 4 bpm ; night: 86 +/- 2 bpm). Concomitantly, the efficiency of spontaneous baroreflex decreased at 6 weeks (36 +/- 1 vs 42 +/- 2 mmHg/ms, p < 0.05). A significant decrease in HF energy of HRV was found after 6 but not after 9 weeks. LF energy of SBPV was increased at 6 but not at 9 weeks (table). [table: see text] In conclusion, this study shows that an hyperlipidic and hypercaloric diet induces transient variations in autonomic nervous system activity which could be the physiopathological link between obesity, insulin-resistance and arterial hypertension.

[Functional decoupling of left ventricular beta-adrenoceptor in a canine model of obesity-hypertension]. / Découplage fonctionnel des récepteurs beta-adrénergiques ventriculaires gauches dans un modèle canin d'obésité-hypertension.

OBJECTIVE: To assess cardiac beta-adrenoceptors (beta-AR) in an obesity-hypertension model. METHODS: Six male beagle dogs (aged 35 +/- 5 months) receiving during 30 weeks a high-fat diet with 60% uncooked beef fat were compared to 6 normal beagle dogs. With right auricular and left ventricular samples we analysed cardiac beta-AR density through binding study using [125I]-cyanopindolol. beta 1 and beta 2 densities were obtained by competition with CGP 20712A. Affinity state of beta-AR was assessed by competition with isoproterenol. Noradrenaline plasma level was assayed by HPLC. Left ventricular mass (LV mass) was measured by echocardiography. Results are expressed as mean +/- SE. All comparisons were performed using a variance analysis (*: p < 0.05). RESULTS: Systolic blood pressure was significantly higher in obesses (245 +/- 8 vs 197 +/- 10 mmHg in controls). Diastolic blood pressure did not differed between both groups (93 +/- 3 vs 84 +/- 3 mmHg in controls). Noradrenaline plasma levels were similar in both groups (276 +/- 30 vs 235 +/- 50 pg/mL in controls). Obesses were characterized by higher LV mass (80 +/- 24 vs 67 +/- 15 g in controls*). Right auricular and left ventricular beta-AR densities were not different in obesses (57 +/- 6 and 67 +/- 4 fmoles/mg protein) and in controls (68 +/- 7 and 63 +/- 9 fmoles/mg protein). The beta 1-AR proportion was the same in obesses and controls in right auricule (63 +/- 4 vs 64 +/- 3% in controls) and left ventricule (59 +/- 3 vs 60 +/- 4% in controls). The proportion of beta-AR receptors in a high affinity state was similar in right auricular samples (69 +/- 4 vs 67 +/- 3%) in controls) but was significantly different in left ventricule (28 +/- 6 vs 74 +/- 6%) in controls). CONCLUSION: Left ventricular beta-adrenoceptors came under a specific desensibilisation independent of plasma noradrenaline levels. This functional decoupling of beta-adrenoceptors may account for the progressive systolic dysfunction of hypertensive cardiomyopathy.

Efficacy and low vascular toxicity of embolization with radical versus anionic polymerization of n-butyl-2-cyanoacrylate (NBCA). An experimental study in the swine.

BACKGROUND AND PURPOSE: To compare the efficacy and vascular toxicity of embolization with radical (NBCA+metacryloxysulpholane=CS) versus conventional anionic (NBCA alone=CA) polymerization of NBCA. MATERIALS AND METHODS: Under continuous digital subtracted angiography (DSA) recordings, a 0.2 mL volume of identical glue mixtures were injected in a single-step procedure, concomitantly, in left and right (with CS and CA, respectively) renal arterial branches (RAB) and ascending pharyngeal arteries (APA) in 8 swines. Arterial histopathology and morphometry of inflammation were investigated at 2 weeks. RESULTS: Complete embolization was achieved with equivalent cast homogeneity on DSA with both NBCA mixtures in RAB and APA. Inflammatory crowns in APA and RAB were significantly lower in CS - than in CA-treated sites (p<0.001). CS plug was scarcely adhesive to the vascular wall, and pulled apart from the wall by a residual thrombotic lining; in contrast with CA casts that were strongly adhesive to walls with endothelium stripping. CONCLUSIONS: Anionic and radical polymerization of NBCA embolization was identical with regards to occlusion rate; whereas radical pathway of polymerization with cyanoacrylates lowered histotoxicity with a less sustained adhesiveness of casts against vascular walls.

QT interval dispersion as a predictor of arrhythmic events in congestive heart failure. Importance of aetiology.

AIMS: Identification of patients with congestive heart failure at risk of sudden death remains problematic and few data are available on the prognostic implications of QT dispersion. We sought to assess the predictive value of QT dispersion for arrhythmic events in heart failure secondary to dilated cardiomyopathy or ischaemic heart disease. METHODS AND RESULTS: Twelve-lead ECGs calculated for QT dispersion, 24 h Holter ECGs and signal-averaged ECGs were prospectively recorded in 205 heart failure patients in sinus rhythm. The 86 patients with ischaemic heart disease and the 119 with dilated cardiomyopathy were not significantly different as regards NYHA grades (51 vs 49% in grades III-i.v.), cardiothoracic ratio (57 +/- 7 vs 57 +/- 6%) and ejection fraction (28 +/- 8 vs 29 +/- 9%). The mean QT dispersion (66 +/- 29 vs 65 +/- 27 ms), the frequency of non-sustained ventricular tachycardia (37 vs 38%) and ventricular late potentials (41 vs 40%) were not significantly different in patients with ischaemic or dilated cardiomyopathy. QT dispersion was significantly related to other arrhythmogenic markers. During follow-up (24 +/- 16 months), 66 patients died, 22 of them died suddenly and seven presented a spontaneous sustained ventricular tachycardia. In patients with dilated cardiomyopathy, in multivariate analysis, only a QT dispersion > 80 ms was an independent predictor of sudden death (RR: 4.9, 95% CI 1.4-16.8, P < 0.02) and arrhythmic events (RR: 4.5, 95% CI 1.5-13.5, P < 0.01). In patients with ischaemic heart disease, no studied parameter was found significantly related to sudden death or arrhythmic events. CONCLUSIONS: In congestive heart failure, abnormal QT dispersion can identify patients with dilated cardiomyopathy who are at high risk of arrhythmic events.